Abstract. G protein-coupled receptors (GPCRs) constitute one of the largest families of cell surface receptors and regulate many aspects of human physiology. The relaxin receptor, RXFP1, is a poorly understood GPCR which is currently being targeted in clinical trials as a therapy for acute heart failure. In these trials, RXFP1 is activated by a recombinant version of its endogenous agonist, the small protein hormone relaxin-2. Binding of relaxin-2 to RXFP1 induces pleiotropic cellular responses, including vasodilation, angiogenesis, and extracellular matrix remodeling. These effects in various tissues, particularly the heart, liver, and kidneys, make RXFP1 a promising drug target to treat cardiovascular diseases and multiple diseases of organ fibrosis. Despite the biological importance of RXFP1, relatively little is known about the detailed mechanisms underlying receptor activation by relaxin-2. RXFP1 belongs to the leucine-rich repeat-containing GPCR (LGR) family due to its large ectodomain, which contains ten leucine-rich repeats (LRRs) and a low-density lipoprotein type A module at the N-terminus. The interactions between these domains which couple relaxin-2 binding to intracellular signaling are unknown, largely due to a lack of structural data. Therefore, I will determine the structure of RXFP1 bound to relaxin-2, which will reveal the interactions involved in ligand binding and signal transduction to provide information for future structure-based drug design. A second key objective focuses on the fact that there are very few ligands available to modulate RXFP1 signaling. As a result, it is currently not possible to inactivate RXFP1 signaling or selectively activate specific subsets of the receptor's signaling pathways. The lack of suitable tools to study RXFP1 activation and its cellular consequences have hindered our understanding of the receptor's molecular mechanism and full potential as a therapeutic target. To address this, I will develop novel agonists and antagonists of RXPF1 through protein engineering. Characterization of the ability of these ligands to modulate RXFP1's cellular responses will provide new insights into the receptor's signaling mechanisms and will generate information which can be leveraged for drug development. Collectively, the proposed research will lead to a better understanding of the molecular mechanism of RXFP1 signaling and will improve our ability to translate biomedical interest in RXFP1 into new therapeutics.